Oxetacaine

Oxethazaine (OXZ) is one of the few local anaesthetics that provides analgesia at low pH, but presents poor solubility, cytotoxicity and no parenteral formulations. To address these issues, we aimed to prepare OXZ host-guest inclusion complex with hydroxypropyl-beta-cyclodextrin (HP-β-CD).

The inclusion complex was formed by co-solubilization, followed by a job plot analysis to determine stoichiometry of complexation and dialysis equilibrium analysis (based on UV/VIS absorption and fluorescence profiles of OXZ). Complex formation was confirmed by phase-solubility data, X-ray, Scanning Electron Microscopy and DOSY-1H-NMR experiments. In vitro cytotoxicity was analysed by MTT test in 3T3 fibroblasts. In vivo analgesia was tested by Von Frey test (inflammatory wounds – rats).

Oxethazaine complexed (1 : 1 molar ratio) with HP-β-CD, as indicated by loss of OZX crystalline structure (X-ray) and strong host: guest interaction (NMR, K = 198/m), besides increased solubility. In vitro cell survival improved with the complex (IC50 OXZ = 28.9 μm, OXZ : HP-β-CD = 57.8 μm). In addition, the complex (0.1% OXZ) promoted in vivo analgesia for the same time that 2% lidocaine/epinephrine did.

Our results show that complexation improved physicochemical and biological properties of OXZ, allowing its application to inflamed tissues by parenteral routes.

There have been few reports concerning to the drug-drug interactions (DDIs) with OTC drugs although an increase in the use of OTC drugs in recent years. This current study was conducted to clarify the DDIs through CYP3A inhibition by oxethazaine (OXZ), an antacid available as an OTC drug. Midazolam (MDZ) was used as a probe drug for CYP3A activity. In an in vivo study, a single oral dose of OXZ (50 mg/kg) was administered to rats 30, 60, or 120 min before oral MDZ administration (15 mg/kg). Serum concentrations of MDZ were analyzed by HPLC, and its pharmacokinetic parameters were compared with a water-treated control group. The inhibitory effect of OXZ on MDZ 1'-hydroxylation (MDZ 1'-OH) activity was investigated in vitro using rat liver and intestinal microsomes. Pretreatment of OXZ 120 min before MDZ administration significantly increased the area under the serum concentration-time curve (AUC_0-∞) of MDZ six-fold compared to the control group without a change in elimination half-life (t_1/2). In contrast, OXZ pretreatment 30 or 60 min before MDZ administration did not show any remarkable change in MDZ pharmacokinetic parameters. The in vitro study showed that OXZ inhibited MDZ 1'-OH activity in a concentration-dependent manner both in liver and intestinal microsomes. These results suggested that OXZ increases serum MDZ concentration presumably by the inhibition of liver and/or intestinal CYP3A activity. OXZ was predicted to cause the DDIs mediated by CYP3A inhibition, although this effect depended on the dose interval.